How do ALS-associated TDP-43 mutations produce similar mRNA mislocalization as complete TDP-43 loss?

The abstract reports that disease mutations phenocopy TDP-43 knockout effects on mRNA localization, suggesting a loss-of-function mechanism. However, this contradicts evidence that ALS mutations often cause toxic gain-of-function, requiring mechanistic clarification for therapeutic targeting. Gap type: contradiction Source paper: TDP-43 directly inhibits mRNA accumulation in neurites through modulation of mRNA stability. (2026, The EMBO journal, PMID:41398473)